tbuckley/cabot-search huggingface dataset:
Association between SARS-CoV-2 vaccination and healthcare contacts for menstrual disturbance and bleeding in women before and after menopause: nationwide, register based cohort study
Authors: Rickard Ljung, YiYi Xu, Anders Sundström, Susannah Leach, Ebba Hallberg, Maria Bygdell, Maria Larsson, Veronica Arthurson, Magnus Gisslén, Rolf Gedeborg, Fredrik Nyberg
Journal: BMJ (2023)

To evaluate the risks of any menstrual disturbance and bleeding following SARS-CoV-2 vaccination in women who are premenopausal or postmenopausal.A nationwide, register based cohort study.All inpatient and specialised outpatient care in Sweden from 27 December 2020 to 28 February 2022. A subset covering primary care for 40% of the Swedish female population was also included.2 946 448 Swedish women aged 12-74 years were included. Pregnant women, women living in nursing homes, and women with history of any menstruation or bleeding disorders, breast cancer, cancer of female genital organs, or who underwent a hysterectomy between 1 January 2015 and 26 December 2020 were excluded.SARS-CoV-2 vaccination, by vaccine product (BNT162b2, mRNA-1273, or ChAdOx1 nCoV-19 (AZD1222)) and dose (unvaccinated and first, second, and third dose) over two time windows (one to seven days, considered the control period, and 8-90 days).Healthcare contact (admission to hospital or visit) for menstrual disturbance or bleeding before or after menopause (diagnosed with the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes N91, N92, N93, N95).2 580 007 (87.6%) of 2 946 448 women received at least one SARS-CoV-2 vaccination and 1 652 472 (64.0%) 2 580 007 of vaccinated women received three doses before the end of follow-up. The highest risks for bleeding in women who were postmenopausal were observed after the third dose, in the one to seven days risk window (hazard ratio 1.28 (95% confidence interval 1.01 to 1.62)) and in the 8-90 days risk window (1.25 (1.04 to 1.50)). The impact of adjustment for covariates was modest. Risk of postmenopausal bleeding suggested a 23-33% increased risk after 8-90 days with BNT162b2 and mRNA-1273 after the third dose, but the association with ChAdOx1 nCoV-19 was less clear. For menstrual disturbance or bleeding in women who were premenopausal, adjustment for covariates almost completely removed the weak associations noted in the crude analyses.Weak and inconsistent associations were observed between SARS-CoV-2 vaccination and healthcare contacts for bleeding in women who are postmenopausal, and even less evidence was recorded of an association for menstrual disturbance or bleeding in women who were premenopausal. These findings do not provide substantial support for a causal association between SARS-CoV-2 vaccination and healthcare contacts related to menstrual or bleeding disorders.
Systemic and Intracranial Outcomes With First-Line Nivolumab Plus Ipilimumab in Patients With Metastatic NSCLC and Baseline Brain Metastases From CheckMate 227 Part 1
Authors: Martin Reck, Tudor-Eliade Ciuleanu, Jong-Seok Lee, Michael Schenker, Bogdan Zurawski, Sang-We Kim, Mauricio Mahave, Aurelia Alexandru, Solange Peters, Adam Pluzanski, Reyes Bernabe Caro, Helena Linardou, Jacobus A. Burgers, Makoto Nishio, Alex Martinez-Marti, Koichi Azuma, Rita Axelrod, Luis G. Paz-Ares, Suresh S. Ramalingam, Hossein Borghaei, Kenneth J. O’Byrne, Li Li, Judith Bushong, Ravi G. Gupta, Diederik J. Grootendorst, Laura J. Eccles, Julie R. Brahmer
Journal: Journal of Thoracic Oncology (2023)

In CheckMate 227 Part 1, nivolumab plus ipilimumab prolonged overall survival (OS) versus chemotherapy in patients with metastatic NSCLC, regardless of tumor programmed death-ligand 1 (PD-L1) expression. Here, we report post hoc exploratory systemic and intracranial efficacy outcomes and safety by baseline brain metastasis status at 5 years' minimum follow-up.Treatment-naive adults with stage IV or recurrent NSCLC without EGFR or ALK alterations, including asymptomatic patients with treated brain metastases, were enrolled. Patients with tumor PD-L1 greater than or equal to 1% were randomized to nivolumab plus ipilimumab, nivolumab, or chemotherapy; patients with tumor PD-L1 less than 1% were randomized to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy groups. Assessments included OS, systemic and intracranial progression-free survival per blinded independent central review, new brain lesion development, and safety. Brain imaging was performed at baseline (all randomized patients) and approximately every 12 weeks thereafter (patients with baseline brain metastases only).Overall, 202 of 1739 randomized patients had baseline brain metastases (nivolumab plus ipilimumab: 68; chemotherapy: 66). At 61.3 months' minimum follow-up, nivolumab plus ipilimumab prolonged OS versus chemotherapy in patients with baseline brain metastases (hazard ratio = 0.63; 95% confidence interval: 0.43-0.92) and in those without (hazard ratio = 0.76; 95% confidence interval: 0.66-0.87). In patients with baseline brain metastases, 5-year systemic and intracranial progression-free survival rates were higher with nivolumab plus ipilimumab (12% and 16%, respectively) than chemotherapy (0% and 6%). Fewer patients with baseline brain metastases developed new brain lesions with nivolumab plus ipilimumab (4%) versus chemotherapy (20%). No new safety signals were observed.With all patients off immunotherapy for more than or equal to 3 years, nivolumab plus ipilimumab continued to provide a long-term, durable survival benefit in patients with or without brain metastases. Intracranial efficacy outcomes favored nivolumab plus ipilimumab versus chemotherapy. These results further support nivolumab plus ipilimumab as an efficacious first-line treatment for patients with metastatic NSCLC, regardless of baseline brain metastasis status.
Virological characteristics of the SARS-CoV-2 omicron XBB.1.16 variant
Authors: Daichi Yamasoba, Keiya Uriu, Arnon Plianchaisuk, Yusuke Kosugi, Lin Pan, Jiri Zahradnik, Jumpei Ito, Kei Sato
Journal: The Lancet Infectious Diseases (2023)
Impact of Clonal Architecture on Clinical Course and Prognosis in Patients With Myeloproliferative Neoplasms
Authors: Damien Luque Paz, Michael S. Bader, Ronny Nienhold, Shivam Rai, Tiago Almeida Fonseca, Jan Stetka, Hui Hao-Shen, Gabriele Mild-Schneider, Jakob R. Passweg, Radek C. Skoda
Journal: HemaSphere (2023)

Myeloproliferative neoplasms (MPNs) are caused by a somatic gain-of-function mutation in 1 of the 3 disease driver genes
Organism-wide, cell-type-specific secretome mapping of exercise training in mice
Authors: Wei Wei, Nicholas M. Riley, Xuchao Lyu, Xiaotao Shen, Jing Guo, Steffen H. Raun, Meng Zhao, Maria Dolores Moya-Garzon, Himanish Basu, Alan Sheng-Hwa Tung, Veronica L. Li, Wentao Huang, Amanda L. Wiggenhorn, Katrin J. Svensson, Michael P. Snyder, Carolyn R. Bertozzi, Jonathan Z. Long
Journal: Cell Metabolism (2023)
Gut pathogen colonization precedes bloodstream infection in the neonatal intensive care unit
Authors: Drew J. Schwartz, Nitan Shalon, Kate Wardenburg, Anna DeVeaux, Meghan A. Wallace, Carla Hall-Moore, I. Malick Ndao, Janice E. Sullivan, Paula Radmacher, Marilyn Escobedo, Carey-Ann D. Burnham, Barbara B. Warner, Phillip I. Tarr, Gautam Dantas
Journal: Science Translational Medicine (2023)

Bacterial bloodstream infections (BSIs) resulting in late-onset sepsis affect up to half of extremely preterm infants and have substantial morbidity and mortality. Bacterial species associated with BSIs in neonatal intensive care units (NICUs) commonly colonize the preterm infant gut microbiome. Accordingly, we hypothesized that the gut microbiome is a reservoir of BSI-causing pathogenic strains that increase in abundance before BSI onset. We analyzed 550 previously published fecal metagenomes from 115 hospitalized neonates and found that recent ampicillin, gentamicin, or vancomycin exposure was associated with increased abundance of Enterobacteriaceae and Enterococcaceae in infant guts. We then performed shotgun metagenomic sequencing on 462 longitudinal fecal samples from 19 preterm infants (cases) with BSI and 37 non-BSI controls, along with whole-genome sequencing of the BSI isolates. Infants with BSI caused by Enterobacteriaceae were more likely than infants with BSI caused by other organisms to have had ampicillin, gentamicin, or vancomycin exposure in the 10 days before BSI. Relative to controls, gut microbiomes of cases had increased relative abundance of the BSI-causing species and clustered by Bray-Curtis dissimilarity according to BSI pathogen. We demonstrated that 11 of 19 (58%) of gut microbiomes before BSI, and 15 of 19 (79%) of gut microbiomes at any time, harbored the BSI isolate with fewer than 20 genomic substitutions. Last, BSI strains from the Enterobacteriaceae and Enterococcaceae families were detected in multiple infants, indicating BSI-strain transmission. Our findings support future studies to evaluate BSI risk prediction strategies based on gut microbiome abundance in hospitalized preterm infants.
Therapeutic blocking of VEGF binding to neuropilin-2 diminishes PD-L1 expression to activate antitumor immunity in prostate cancer
Authors: Mengdie Wang, Christi A. Wisniewski, Choua Xiong, Peter Chhoy, Hira Lal Goel, Ayush Kumar, Lihua Julie Zhu, Rui Li, Pamela A. St. Louis, Lindsay M. Ferreira, Hubert Pakula, Zhiwen Xu, Massimo Loda, Zhong Jiang, Michael A. Brehm, Arthur M. Mercurio
Journal: Science Translational Medicine (2023)

Prostate cancers are largely unresponsive to immune checkpoint inhibitors (ICIs), and there is strong evidence that programmed death-ligand 1 (PD-L1) expression itself must be inhibited to activate antitumor immunity. Here, we report that neuropilin-2 (NRP2), which functions as a vascular endothelial growth factor (VEGF) receptor on tumor cells, is an attractive target to activate antitumor immunity in prostate cancer because VEGF-NRP2 signaling sustains PD-L1 expression. NRP2 depletion increased T cell activation in vitro. In a syngeneic model of prostate cancer that is resistant to ICI, inhibition of the binding of VEGF to NRP2 using a mouse-specific anti-NRP2 monoclonal antibody (mAb) resulted in necrosis and tumor regression compared with both an anti–PD-L1 mAb and control immunoglobulin G. This therapy also decreased tumor PD-L1 expression and increased immune cell infiltration. We observed that the NRP2 , VEGFA , and VEGFC genes are amplified in metastatic castration-resistant and neuroendocrine prostate cancer. We also found that individuals with NRP2 High PD-L1 High metastatic tumors had lower androgen receptor expression and higher neuroendocrine prostate cancer scores than other individuals with prostate cancer. In organoids derived from patients with neuroendocrine prostate cancer, therapeutic inhibition of VEGF binding to NRP2 using a high-affinity humanized mAb suitable for clinical use also diminished PD-L1 expression and caused a substantial increase in immune-mediated tumor cell killing, consistent with the animal studies. These findings provide justification for the initiation of clinical trials using this function-blocking NRP2 mAb in prostate cancer, especially for patients with aggressive disease.
Pathophysiology of Dyt1- <i>Tor1a</i> dystonia in mice is mediated by spinal neural circuit dysfunction
Authors: Amanda M. Pocratsky, Filipe Nascimento, M. Görkem Özyurt, Ian J. White, Roisin Sullivan, Benjamin J. O’Callaghan, Calvin C. Smith, Sunaina Surana, Marco Beato, Robert M. Brownstone
Journal: Science Translational Medicine (2023)

Dystonia, a neurological disorder defined by abnormal postures and disorganized movements, is considered to be a neural circuit disorder with dysfunction arising within and between multiple brain regions. Given that spinal neural circuits constitute the final pathway for motor control, we sought to determine their contribution to this movement disorder. Focusing on the most common inherited form of dystonia in humans, DYT1- TOR1A , we generated a conditional knockout of the torsin family 1 member A ( Tor1a ) gene in the mouse spinal cord and dorsal root ganglia (DRG). We found that these mice recapitulated the phenotype of the human condition, developing early-onset generalized torsional dystonia. Motor signs emerged early in the mouse hindlimbs before spreading caudo-rostrally to affect the pelvis, trunk, and forelimbs throughout postnatal maturation. Physiologically, these mice bore the hallmark features of dystonia, including spontaneous contractions at rest and excessive and disorganized contractions, including cocontractions of antagonist muscle groups, during voluntary movements. Spontaneous activity, disorganized motor output, and impaired monosynaptic reflexes, all signs of human dystonia, were recorded from isolated mouse spinal cords from these conditional knockout mice. All components of the monosynaptic reflex arc were affected, including motor neurons. Given that confining the Tor1a conditional knockout to DRG did not lead to early-onset dystonia, we conclude that the pathophysiological substrate of this mouse model of dystonia lies in spinal neural circuits. Together, these data provide new insights into our current understanding of dystonia pathophysiology.
Inhibition of VEGF binding to neuropilin-2 enhances chemosensitivity and inhibits metastasis in triple-negative breast cancer
Authors: Zhiwen Xu, Hira Lal Goel, Christoph Burkart, Luke Burman, Yeeting E. Chong, Alison G. Barber, Yanyan Geng, Liting Zhai, Mengdie Wang, Ayush Kumar, Ann Menefee, Clara Polizzi, Lisa Eide, Kaitlyn Rauch, Justin Rahman, Kristina Hamel, Zachary Fogassy, Sofia Klopp-Savino, Suzanne Paz, Mingjie Zhang, Andrea Cubitt, Leslie A. Nangle, Arthur M. Mercurio
Journal: Science Translational Medicine (2023)

Although blocking the binding of vascular endothelial growth factor (VEGF) to neuropilin-2 (NRP2) on tumor cells is a potential strategy to treat aggressive carcinomas, a lack of effective reagents that can be used clinically has hampered this potential therapy. Here, we describe the generation of a fully humanized, high-affinity monoclonal antibody (aNRP2-10) that specifically inhibits the binding of VEGF to NRP2, conferring antitumor activity without causing toxicity. Using triple-negative breast cancer as a model, we demonstrated that aNRP2-10 could be used to isolate cancer stem cells (CSCs) from heterogeneous tumor populations and inhibit CSC function and epithelial-to-mesenchymal transition. aNRP2-10 sensitized cell lines, organoids, and xenografts to chemotherapy and inhibited metastasis by promoting the differentiation of CSCs to a state that is more responsive to chemotherapy and less prone to metastasis. These data provide justification for the initiation of clinical trials designed to improve the response of patients with aggressive tumors to chemotherapy using this monoclonal antibody.
Paradoxes of Cellular SUMOylation Regulation: A Role of Biomolecular Condensates?
Authors: Xiaodong Cheng, Wenli Yang, Wei Lin, Fang Mei
Journal: Pharmacological Reviews (2023)

Protein SUMOylation is a major post-translational modification important for maintaining cellular homeostasis. SUMOylation has long been associated with stress responses as a diverse array of cellular stress signals are known to trigger rapid alternations in global protein SUMOylation. In addition, while there are large families of ubiquitination enzymes, all SUMOs are conjugated by a set of enzymatic machinery comprising one heterodimeric SUMO-activating enzyme, a single SUMO-conjugating enzyme, and a small number of SUMO protein ligases and SUMO-specific proteases. How a few SUMOylation enzymes specifically modify thousands of functional targets in response to diverse cellular stresses remains an enigma. Here, we review recent progress toward understanding the mechanisms of SUMO regulation, particularly, the potential roles of liquid-liquid phase separation/biomolecular condensates in the regulation of cellular SUMOylation during cellular stresses. In addition, we discuss the role of protein SUMOylation in pathogenesis and the development of novel therapeutics targeting SUMOylation. <b>Significance Statement</b> Protein SUMOylation is one of the most prevalent post-translational modifications and plays an important role in maintaining cellular homeostasis in response to stresses. Protein SUMOylation has been implicated in human pathogenesis such as cancer, cardiovascular diseases, neurodegeneration, and infection. After more than a quarter century of extensive research, intriguing enigmas remain regarding the mechanism of cellular SUMOylation regulation and the therapeutic potential of targeting SUMOylation.
Intravenous N-Acetylcysteine to Prevent Cisplatin-Induced Hearing Loss in Children: A Nonrandomized Controlled Phase I Trial
Authors: Etan Orgel, Kristin R. Knight, Yueh-Yun Chi, Jemily Malvar, Teresa Rushing, Victoria Mena, Laurie S. Eisenberg, Shahrad R. Rassekh, Colin J.D. Ross, Erika N. Scott, Michael Neely, Edward A. Neuwelt, Leslie L. Muldoon, David R. Freyer
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Cisplatin-induced hearing loss (CIHL) is common and permanent. As compared with earlier otoprotectants, we hypothesized N-acetylcysteine (NAC) offers potential for stronger otoprotection through stimulation of glutathione (GSH) production. This study tested the optimal dose, safety, and efficacy of NAC to prevent CIHL. Patients and Methods: In this nonrandomized, controlled phase Ia/Ib trial, children and adolescents newly diagnosed with nonmetastatic, cisplatin-treated tumors received NAC intravenously 4 hours post-cisplatin. The trial performed dose-escalation across three dose levels to establish a safe dose that exceeded the targeted peak serum NAC concentration of 1.5 mmol/L (as identified from preclinical models). Patients with metastatic disease or who were otherwise ineligible were enrolled in an observation-only/control arm. To evaluate efficacy, serial age-appropriate audiology assessments were performed. Integrated biology examined genes involved in GSH metabolism and post-NAC GSH concentrations. Results: Of 52 patients enrolled, 24 received NAC and 28 were in the control arm. The maximum tolerated dose was not reached; analysis of peak NAC concentration identified 450 mg/kg as the recommended phase II dose (RP2D). Infusion-related reactions were common. No severe adverse events occurred. Compared with the control arm, NAC decreased likelihood of CIHL at the end of cisplatin therapy [OR, 0.13; 95% confidence interval (CI), 0.021–0.847; P = 0.033] and recommendations for hearing intervention at end of study (OR, 0.082; 95% CI, 0.011–0.60; P = 0.014). NAC increased GSH; GSTP1 influenced risk for CIHL and NAC otoprotection. Conclusions: NAC was safe at the RP2D, with strong evidence for efficacy to prevent CIHL, warranting further development as a next-generation otoprotectant.
<i>Ezh2</i> knockout in B cells impairs plasmablast differentiation and ameliorates lupus‐like disease in MRL/lpr mice: comment on the article by Zheng et al
Authors: An‐Fang Huang, Wang‐Dong Xu
Journal: Arthritis & Rheumatology (2023)

Disclosure Form Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Sirtuin 6 is required for the integrated stress response and resistance to inhibition of transcriptional cyclin-dependent kinases
Authors: Nithya Kartha, Jessica E. Gianopulos, Zachary Schrank, Sarah M. Cavender, Stephanie Dobersch, Bryan D. Kynnap, Adrianne Wallace-Povirk, Cynthia L. Wladyka, Juan F. Santana, Jaeseung C. Kim, Angela Yu, Caroline M. Bridgwater, Kathrin Fuchs, Sarah Dysinger, Aaron E. Lampano, Faiyaz Notta, David H. Price, Andrew C. Hsieh, Sunil R. Hingorani, Sita Kugel
Journal: Science Translational Medicine (2023)

Pancreatic ductal adenocarcinoma (PDAC) is classified into two key subtypes, classical and basal, with basal PDAC predicting worse survival. Using in vitro drug assays, genetic manipulation experiments, and in vivo drug studies in human patient-derived xenografts (PDXs) of PDAC, we found that basal PDACs were uniquely sensitive to transcriptional inhibition by targeting cyclin-dependent kinase 7 (CDK7) and CDK9, and this sensitivity was recapitulated in the basal subtype of breast cancer. We showed in cell lines, PDXs, and publicly available patient datasets that basal PDAC was characterized by inactivation of the integrated stress response (ISR), which leads to a higher rate of global mRNA translation. Moreover, we identified the histone deacetylase sirtuin 6 (SIRT6) as a critical regulator of a constitutively active ISR. Using expression analysis, polysome sequencing, immunofluorescence, and cycloheximide chase experiments, we found that SIRT6 regulated protein stability by binding activating transcription factor 4 (ATF4) in nuclear speckles and protecting it from proteasomal degradation. In human PDAC cell lines and organoids as well as in murine PDAC genetically engineered mouse models where SIRT6 was deleted or down-regulated, we demonstrated that SIRT6 loss both defined the basal PDAC subtype and led to reduced ATF4 protein stability and a nonfunctional ISR, causing a marked vulnerability to CDK7 and CDK9 inhibitors. Thus, we have uncovered an important mechanism regulating a stress-induced transcriptional program that may be exploited with targeted therapies in particularly aggressive PDAC.
Quadriceps or hip exercises for patellofemoral pain? A randomised controlled equivalence trial
Authors: Rudi Hansen, Christoffer Brushøj, Michael Skovdal Rathleff, S Peter Magnusson, Marius Henriksen
Journal: British Journal of Sports Medicine (2023)

To assess effectiveness equivalence between two commonly prescribed 12-week exercise programmes targeting either the quadriceps or the hip muscles in patients with patellofemoral pain (PFP).This randomised controlled equivalence trial included patients with a clinical diagnosis of PFP. Participants were randomly assigned to either a 12-week quadriceps-focused exercise (QE) or a hip-focused exercise (HE) programme. The primary outcome was the change in Anterior Knee Pain Scale (AKPS) (0-100) from baseline to 12-week follow-up. Prespecified equivalence margins of ±8 points on the AKPS were chosen to demonstrate comparable effectiveness. Key secondary outcomes were the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire pain, physical function and knee-related quality of life subscales.200 participants underwent randomisation; 100 assigned to QE and 100 to HE (mean age 27.2 years (SD 6.4); 69% women). The least squares mean changes in AKPS (primary outcome) were 7.6 for QE and 7.0 for HE (difference 0.6 points, 95% CI -2.0 to 3.2; test for equivalence p<0.0001), although neither programme surpassed the minimal clinically important change threshold. None of the group differences in key secondary outcomes exceeded predefined equivalence margins.The 12-week QE and HE protocols provided equivalent improvements in symptoms and function for patients with PFP.NCT03069547.